The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
The term “cardiorenal syndrome” refers to a physiologic relationship between the heart and kidney that manifests as a tight coordination between renal and cardiac functions in subjects suffering from heart failure. While the syndrome is poorly understood, a feedback loop amongst neurohormonal systems (and, in particular, the natriuretic peptides), inflammatory responses, and structurally and functionally impaired organs has been implicated, creating a cycle of worsening cardiac and renal functions. A recent discussion of cardiorenal syndrome may be found in Francis, “Acute decompensated heart failure: The cardiorenal syndrome,” Clev. Clinic J. Med. 73(S2): S8-S13, 2006.
In heart failure patients, the onset of renal dysfunction has proved a strong risk factor for mortality. In fact, an increased risk is signaled even at serum creatinine levels >1.3 mg/dL and estimated creatinine clearance values ≦60 to 70 mL/min, values that can fall within “normal” values for each of these parameters. Although renal dysfunction predicts all-cause mortality, it is most predictive of death from progressive heart failure, which suggests that it is a manifestation of and/or exacerbating factor for left ventricular dysfunction. And worsening renal function may be even more important than baseline renal function for predicting adverse outcomes. In one multicenter study, a serum creatinine increase of ≧0.3 mg/dL had a sensitivity of 65% and specificity of 81% for predicting in-hospital mortality. Gottlieb et al., “The prognostic importance of different definitions of worsening renal function in congestive heart failure,” J. Card. Fail. 8: 136-141, 2002. Other studies have reported that deteriorating renal function is associated with a longer length of stay, an increased risk of death within 6 months after discharge, and a 33% increased risk for hospital readmission.
In addition, numerous studies have demonstrated that a variety of heart failure therapies may actually worsen renal function, triggering a deterioration in the cardiorenal axis. For example, certain diuretics have been associated with worsening renal function, especially in the presence of ACE inhibitors, and high diuretic doses have been associated with increased mortality rates. This is often thought to result from “diuretic resistance,” e.g., a failure to excrete at least 90 mmol of sodium within 72 hours of a 160 mg oral furosemide dose given twice daily, which necessitates increasing diuretic dosage. Whatever the cause, the resulting volume overload is poorly tolerated and a frequent cause of hospital admission in patients with heart failure.
In patients exhibiting worsening renal function, volume overload, and diuretic refractoriness, the management of cardiorenal disease can be extremely difficult. Positive inotropic agents (including dobutamine, phosphodiesterase inhibitors, and levosimendan) may facilitate a diuresis with preservation or improvement in renal function. Although dopamine also is used because of its presumed ability to improve renal blood flow, this effect is severely limited in advanced heart failure. Intravenous vasodilators can improve hemodynamics, but often will not improve renal function.
In recent years, natriuretic peptide measurement has dramatically changed the diagnosis and management of cardiac diseases, including heart failure and the acute coronary syndromes. In particular, B-type natriuretic peptide (BNP, human precursor Swiss-Prot P16860), and various related polypeptides arising from the common precursor proBNP, have been used to diagnose heart failure, determine its severity, and estimate prognosis. In addition, BNP and its related polypeptides have been demonstrated to provide diagnostic and prognostic information in unstable angina, non-ST-elevation myocardial infarction, and ST-elevation myocardial infarction.
In contrast, current diagnostic tests for renal dysfunction, such as serum creatinine or cystatin C measurements, can be misleading to the clinician. While it is preferred that aggressive treatment begin at the earliest indication of renal dysfunction, these tests may only become abnormal days after the original insult. A large proportion of the renal mass may be damaged before any biochemical evidence of renal dysfunction is appreciated, as the rise of serum creatinine may not be evident before 50% of the glomerular filtration rate is lost. No surprisingly perhaps, it has been reported that about two thirds of the patients admitted for acute heart failure have inadequate glomerular filtration rates or creatinine clearance, despite relatively normal serum creatinine levels. Recently, NGAL (also known as neutrophil gelatinase-associated lipocalin, human precursor Swiss-Prot P80188) has been proposed as a new early marker for acute renal injury, with reports of increased levels of NGAL from acute renal injury detectable in both urine and blood within two hours of the insult. See, e.g., WO04088276; WO05121788; WO06066587. The use of NGAL as a risk marker in the context of heart failure, renal dysfunction, or cardiorenal syndrome has not been described.